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Purpose: We sought to determine whether administration of a MGMT blocker, O⁶-benzyl guanine (O⁶BG), at an optimal biological dose alone or in combination with gemcitabine inhibits human pancreatic cancer cell growth.

Experimental Design: Human pancreatic cancer L3.6pl and PANC1 cells were treated with O⁶BG, either alone or in combination with gemcitabine, and the therapeutic efficacy and biological activity of these drug combinations were investigated.

Results: O⁶BG sensitized pancreatic cancer cells to gemcitabine. Protein and mRNA expression of MGMT, cyclin B1, cyclin B2, cyclin A, and ki-67 were significantly decreased in the presence of O⁶BG. In sharp contrast, protein expression and mRNA message of p21^cip1 were significantly increased. Interestingly, O⁶BG increases p53-mediated p21^cip1 transcriptional activity and suppresses cyclin B1. In addition, our …